Centrally and Peripherally Administered Ghrelin Potently Inhibits Water Intake in Rats

Hashimoto, Hirofumi; Fujihara, Hiroaki; Kawasaki, Makoto; Saito, Takeshi; Shibata, Minori; Otsubo, Hiroki; Takei, Yoshiyuki; Ueta, Yoichi

doi:10.1210/en.2006-0993

Cited by 76 publications

(90 citation statements)

References 50 publications

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“…This indicates that while AP neurons are in free contact with circulating hormones such as ghrelin, other adjacent caudal brain stem areas, such as the NTS and dorsal motor nucleus are functionally isolated from the circulation. Activation of neurons in the NTS and other brain stem sites by peripheral ghrelin (24,56) is likely to be secondary to modulation of AP neurons (38). Together with the present results, these data suggest that AP is the primary sensor of ghrelin in the caudal brain stem.…”

Section: Examples Of Results From Nonresponding Neurons (A) Hyperpolsupporting

confidence: 75%

“…Injection of ghrelin into the NTS or nearby areas stimulated feeding at doses below the threshold required for forebrain injections (17). Many investigators observe that peripheral administration of ghrelin also caused increases in caudal brain stem c-Fos immunoreactivity (24,37,38,56), although such changes have not been reported in all studies (34). Moreover, recent observations by Gilg and Lutz (21) have convincingly demonstrated a role for AP in ghrelin-mediated feeding.…”

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confidence: 99%

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Ghrelin modulates electrical activity of area postrema neurons

Fry¹,

Ferguson²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Ghrelin, a peptide hormone secreted from the stomach, is known to have a potent appetite-stimulating activity. Recently, it has been shown that area postrema (AP), a caudal brain stem center that lacks a blood-brain barrier, is a key site of activity for ghrelin in stimulating appetite and regulating pancreatic protein secretion. In this study, we have examined the ability of ghrelin to regulate the electrical activity of area postrema neurons using patch-clamp electrophysiology. Using current-clamp configuration, we found that at a concentration of 10 nM, ghrelin caused inhibition in 19% of neurons tested, while a further 19% were excited by similar application of ghrelin. The remaining 62% of AP neurons were insensitive to ghrelin. These effects were concentration dependent, with an apparent EC 50 of 1.9 nM. Voltage-clamp recordings revealed that ghrelin caused a potentiation of voltage-gated K ϩ currents in neurons that exhibited a hyperpolarization and a potentiation of a depolarizing nonspecific cation current (NSCC) in those neurons that exhibited a depolarization of membrane potential. These are the first data showing that ghrelin exerts a direct effect on electrical activity of AP neurons and supports the notion that ghrelin can act via the AP to regulate energy homeostasis. patch clamp; action potential; sensory circumventricular organ; energy homeostasis GHRELIN IS AN ACYLATED 28-amino acid peptide hormone, which was discovered on the basis of its activity as an endogenous ligand for the growth hormone secretagogue receptor (GHSR) (35). Originally isolated from the stomach, ghrelin has also been shown to be expressed in various tissues, including the duodenum, adrenal gland, lung, and gonads (22), as well as in neurons in the hypothalamus (11). In addition to its role in the stimulation of growth hormone release in the pituitary, ghrelin is thought to play several roles in the regulation of energy balance. Circulating levels of ghrelin are increased in the fasting state and in anticipation of food (2, 12, 13). Conversely, ghrelin levels are attenuated by feeding and the presence of nutrients in the stomach (58), or by treatment with leptin (2). Administration of ghrelin potently stimulates food intake in rats (58, 64, 65), mice (2), and humans (63). These studies suggest a physiological role in initiation of feeding. Ghrelin is also suggested to play a role in long-term regulation of energy balance, as chronic administration of ghrelin causes weight gain by reducing fat utilization as an energy source (58). Lastly, ghrelin also plays a role in the digestion of food and the stimulation of gastric motility, acid secretion, and pancreatic protein secretion (38, 41).There is considerable interest as to the mechanism by which ghrelin exerts its appetite-stimulating effects, and, in particular, the site of action of ghrelin in the central nervous system (CNS). For example, the neuropeptide Y/Agouti-related peptide (NPY/AGRP) neurons within the arcuate nucleus of the hypothalamus (ARC) are suggested by many t...

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Section: Examples Of Results From Nonresponding Neurons (A) Hyperpolsupporting

confidence: 75%

mentioning

confidence: 99%

Ghrelin modulates electrical activity of area postrema neurons

Fry¹,

Ferguson²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Ghrelin also increases appetite in rats (32), and the orexigenic effect is diminished after lesion to the AP (6). In water-deprived rats, peripheral injections of ghrelin inhibits water intake with the activation of AP neurons but not those of the SFO and OVLT (8). In this study, the antidipsogenic effect of peripherally injected ANP and ghrelin in eels was almost completely abolished after APx as was previously shown for ANP (44).…”

Section: Discussionsupporting

confidence: 85%

“…Ghrelin secreted from the stomach was shown to be a potent antidipsogenic hormone in rats and eels (8,25) and is as potent an antidipsogen as ANP when administered peripherally (Kaiya H and unpublished data). Ghrelin also increases appetite in rats (32), and the orexigenic effect is diminished after lesion to the AP (6).…”

Section: Discussionmentioning

confidence: 98%

The area postrema in hindbrain is a central player for regulation of drinking behavior in Japanese eels

Nobata

Takei

2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Nobata S, Takei Y. The area postrema in hindbrain is a central player for regulation of drinking behavior in Japanese eels. Am J Physiol Regul Integr Comp Physiol 300: R1569 -R1577, 2011. First published March 30, 2011 doi:10.1152/ajpregu.00056.2011It is recognized that fish will drink the surrounding water by reflex swallowing without a thirst sensation. We evaluated the role of the area postrema (AP), a sensory circumventricular organ (CVO) in the medulla oblongata, in the regulation of drinking behavior of seawater (SW) eels. The antidipsogenic effects of ghrelin and atrial natriuretic peptide and hypervolemia and hyperosmolemia (1 M sucrose or 10% NaCl) as well as the dipsogenic effects of angiotensin II and hypovolemia (hemorrhage) were profoundly diminished after AP lesion (APx) in eels compared with sham controls. However, the antidipsogenic effect of urotensin II was not influenced by APx, possibly due to the direct baroreflex inhibition on the swallowing center in eels. When ingested water was drained via an esophageal fistula, water intake increased 30-fold in sham controls but only fivefold in APx eels, suggesting a role for the AP in continuous regulation of drinking by SW eels. After transfer from freshwater to SW, APx eels responded normally with an immediate burst of drinking, but after 4 wk these animals showed a much greater increase in plasma osmolality than controls, suggesting that the AP is involved in acclimation to SW by fine tuning of the drinking rate. Taken together, the AP in the hindbrain of eels plays an integral role in SW acclimation, acting as a conduit of information from plasma for the regulation of drinking, probably without a thirst sensation. This differs from mammals in which sensory CVOs in the forebrain play pivotal roles in thirst regulation. dehydration; ghrelin; angiotensin; circumventricular organ; thirst IN VERTEBRATES, COMPOSITION and volume of the extracellular and intracellular fluids is regulated by behavioral and physiological mechanisms that have been obtained over the course of evolution. Osmoregulators maintain osmolality of the extracellular fluid near a set point value regardless of environmental conditions, which is achieved by balancing the gain and loss of water and ions (3). Among the vertebrate osmoregulators, it is the fishes whose extracellular fluid osmolality is most influenced by the environment, since, either in freshwater (FW) or seawater (SW), they are in direct contact with the environmental medium via respiratory epithelia. In regard to water regulation in FW fishes, excretion is more important than ingestion as FW fishes face constant osmotic gain of water. In contrast, fishes in SW have to drink water constantly to compensate for the osmotic loss of water across body surfaces (5,11,34). In fact, eels that are prevented from drinking die of severe cellular and extracellular dehydration 5 days after SW transfer (38). Previous findings indicate that regulation of drinking is crucial for survival of teleost fishes in SW and that euryhaline fish...

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“…Centrally and peripherally administered acyl ghrelin potently inhibits water intake in rats (Hashimoto et al, 2007), whereas intracerebroventricular acyl ghrelin attenuated water intake stimulated under dipsogenic conditions, such as short-term injection of angitension II or hypertonic saline (Mietlicki et al, 2009), indicating that the actions of acyl ghrelin are not limited to food intake but can also include alterations in water intake. Intracerebroventricular acyl ghrelin also inhibited water intake in chicks under ad libitum and 17-h waterdeprived conditions, suggesting that acyl ghrelin acts as an antidipsogenic peptide across species (Tachibana et al, 2006).…”

Section: Regulation Of Water Intake By Acyl Ghrelinmentioning

confidence: 97%